Estrogen receptor

estrogen receptor 2 (ER-beta)
	A dimer of the ligand-binding region of ERβ (PDB rendering based on 1u3s).
Identifiers
Symbol	ESR2
Alt. symbols	ER-β, NR3A2
NCBI gene	2100
HGNC	3468
OMIM	601663
PDB	1QKM
RefSeq	NM_001040275
UniProt	Q92731
Other data
Locus	Chr. 14 q21-q22
Search for
Structures	Swiss-model
Domains	InterPro

Search for
Structures	Swiss-model
Domains	InterPro

estrogen receptor 1 (ER-alpha)
	A dimer of the ligand-binding region of ERα (PDB rendering based on 3erd).
Identifiers
Symbol	ESR1
Alt. symbols	ER-α, NR3A1
NCBI gene	2099
HGNC	3467
OMIM	133430
PDB	1ERE
RefSeq	NM_000125
UniProt	P03372
Other data
Locus	Chr. 6 q24-q27
Search for
Structures	Swiss-model
Domains	InterPro

Estrogen receptors (ERs) are a group of proteins found inside cells. They are receptors that are activated by the hormone estrogen (17β-estradiol).[1] Two classes of ER exist: nuclear estrogen receptors (ERα and ERβ), which are members of the nuclear receptor family of intracellular receptors, and membrane estrogen receptors (mERs) (GPER (GPR30), ER-X, and G_q-mER), which are mostly G protein-coupled receptors. This article refers to the former (ER).

Once activated by estrogen, the ER is able to translocate into the nucleus and bind to DNA to regulate the activity of different genes (i.e. it is a DNA-binding transcription factor). However, it also has additional functions independent of DNA binding.[2]

As hormone receptors for sex steroids (steroid hormone receptors), ERs, androgen receptors (ARs), and progesterone receptors (PRs) are important in sexual maturation and gestation.

Proteomics

There are two different forms of the estrogen receptor, usually referred to as α and β, each encoded by a separate gene (ESR1 and ESR2, respectively). Hormone-activated estrogen receptors form dimers, and, since the two forms are coexpressed in many cell types, the receptors may form ERα (αα) or ERβ (ββ) homodimers or ERαβ (αβ) heterodimers.[3] Estrogen receptor alpha and beta show significant overall sequence homology, and both are composed of five domains designated A/B through F (listed from the N- to C-terminus; amino acid sequence numbers refer to human ER).

The domain structures of ERα and ERβ, including some of the known phosphorylation sites involved in ligand-independent regulation.

The N-terminal A/B domain is able to transactivate gene transcription in the absence of bound ligand (e.g., the estrogen hormone). While this region is able to activate gene transcription without ligand, this activation is weak and more selective compared to the activation provided by the E domain. The C domain, also known as the DNA-binding domain, binds to estrogen response elements in DNA. The D domain is a hinge region that connects the C and E domains. The E domain contains the ligand binding cavity as well as binding sites for coactivator and corepressor proteins. The E-domain in the presence of bound ligand is able to activate gene transcription. The C-terminal F domain function is not entirely clear and is variable in length.

Estrogen receptor alpha
N-terminal AF1 domain

Identifiers

Symbol

Oest_recep

1hcp / SCOPe / SUPFAM

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Estrogen and estrogen related receptor C-terminal domain

Identifiers

Symbol

ESR1_C

Pfam

PF12743

Available protein structures:
Pfam	structures / ECOD
PDB	RCSB PDB; PDBe; PDBj
PDBsum	structure summary

Due to alternative RNA splicing, several ER isoforms are known to exist. At least three ERα and five ERβ isoforms have been identified. The ERβ isoforms receptor subtypes can transactivate transcription only when a heterodimer with the functional ERß1 receptor of 59 kDa is formed. The ERß3 receptor was detected at high levels in the testis. The two other ERα isoforms are 36 and 46kDa.[4][5]

Only in fish, but not in humans, an ERγ receptor has been described.[6]

Genetics

In humans, the two forms of the estrogen receptor are encoded by different genes, ESR1 and ESR2 on the sixth and fourteenth chromosome (6q25.1 and 14q23.2), respectively.

Distribution

Both ERs are widely expressed in different tissue types, however there are some notable differences in their expression patterns:[7]

The ERα is found in endometrium, breast cancer cells, ovarian stromal cells, and the hypothalamus.[8] In males, ERα protein is found in the epithelium of the efferent ducts.[9]
The expression of the ERβ protein has been documented in ovarian granulosa cells, kidney, brain, bone, heart,[10] lungs, intestinal mucosa, prostate, and endothelial cells.

The ERs are regarded to be cytoplasmic receptors in their unliganded state, but visualization research has shown that only a small fraction of the ERs reside in the cytoplasm, with most ER constitutively in the nucleus.[11] The "ERα" primary transcript gives rise to several alternatively spliced variants of unknown function.[12]

Ligands

Affinities

Affinities of estrogen receptor ligands for the ERα and ERβ
Ligand	Other names	Relative binding affinities (RBA, %)^a		Absolute binding affinities (K_i, nM)^a		Action
Ligand	Other names	ERα	ERβ	ERα	ERβ	Action
Estradiol	E2; 17β-Estradiol	100	100	0.115 (0.04–0.24)	0.15 (0.10–2.08)	Estrogen
Estrone	E1; 17-Ketoestradiol	16.39 (0.7–60)	6.5 (1.36–52)	0.445 (0.3–1.01)	1.75 (0.35–9.24)	Estrogen
Estriol	E3; 16α-OH-17β-E2	12.65 (4.03–56)	26 (14.0–44.6)	0.45 (0.35–1.4)	0.7 (0.63–0.7)	Estrogen
Estetrol	E4; 15α,16α-Di-OH-17β-E2	4.0	3.0	4.9	19	Estrogen
Alfatradiol	17α-Estradiol	20.5 (7–80.1)	8.195 (2–42)	0.2–0.52	0.43–1.2	Metabolite
16-Epiestriol	16β-Hydroxy-17β-estradiol	7.795 (4.94–63)	50	?	?	Metabolite
17-Epiestriol	16α-Hydroxy-17α-estradiol	55.45 (29–103)	79–80	?	?	Metabolite
16,17-Epiestriol	16β-Hydroxy-17α-estradiol	1.0	13	?	?	Metabolite
2-Hydroxyestradiol	2-OH-E2	22 (7–81)	11–35	2.5	1.3	Metabolite
2-Methoxyestradiol	2-MeO-E2	0.0027–2.0	1.0	?	?	Metabolite
4-Hydroxyestradiol	4-OH-E2	13 (8–70)	7–56	1.0	1.9	Metabolite
4-Methoxyestradiol	4-MeO-E2	2.0	1.0	?	?	Metabolite
2-Hydroxyestrone	2-OH-E1	2.0–4.0	0.2–0.4	?	?	Metabolite
2-Methoxyestrone	2-MeO-E1	<0.001–<1	<1	?	?	Metabolite
4-Hydroxyestrone	4-OH-E1	1.0–2.0	1.0	?	?	Metabolite
4-Methoxyestrone	4-MeO-E1	<1	<1	?	?	Metabolite
16α-Hydroxyestrone	16α-OH-E1; 17-Ketoestriol	2.0–6.5	35	?	?	Metabolite
2-Hydroxyestriol	2-OH-E3	2.0	1.0	?	?	Metabolite
4-Methoxyestriol	4-MeO-E3	1.0	1.0	?	?	Metabolite
Estradiol sulfate	E2S; Estradiol 3-sulfate	<1	<1	?	?	Metabolite
Estradiol disulfate	Estradiol 3,17β-disulfate	0.0004	?	?	?	Metabolite
Estradiol 3-glucuronide	E2-3G	0.0079	?	?	?	Metabolite
Estradiol 17β-glucuronide	E2-17G	0.0015	?	?	?	Metabolite
Estradiol 3-gluc. 17β-sulfate	E2-3G-17S	0.0001	?	?	?	Metabolite
Estrone sulfate	E1S; Estrone 3-sulfate	<1	<1	>10	>10	Metabolite
Estradiol benzoate	EB; Estradiol 3-benzoate	10	?	?	?	Estrogen
Estradiol 17β-benzoate	E2-17B	11.3	32.6	?	?	Estrogen
Estrone methyl ether	Estrone 3-methyl ether	0.145	?	?	?	Estrogen
ent-Estradiol	1-Estradiol	1.31–12.34	9.44–80.07	?	?	Estrogen
Equilin	7-Dehydroestrone	13 (4.0–28.9)	13.0–49	0.79	0.36	Estrogen
Equilenin	6,8-Didehydroestrone	2.0–15	7.0–20	0.64	0.62	Estrogen
17β-Dihydroequilin	7-Dehydro-17β-estradiol	7.9–113	7.9–108	0.09	0.17	Estrogen
17α-Dihydroequilin	7-Dehydro-17α-estradiol	18.6 (18–41)	14–32	0.24	0.57	Estrogen
17β-Dihydroequilenin	6,8-Didehydro-17β-estradiol	35–68	90–100	0.15	0.20	Estrogen
17α-Dihydroequilenin	6,8-Didehydro-17α-estradiol	20	49	0.50	0.37	Estrogen
Δ⁸-Estradiol	8,9-Dehydro-17β-estradiol	68	72	0.15	0.25	Estrogen
Δ⁸-Estrone	8,9-Dehydroestrone	19	32	0.52	0.57	Estrogen
Ethinylestradiol	EE; 17α-Ethynyl-17β-E2	120.9 (68.8–480)	44.4 (2.0–144)	0.02–0.05	0.29–0.81	Estrogen
Mestranol	EE 3-methyl ether	?	2.5	?	?	Estrogen
Moxestrol	RU-2858; 11β-Methoxy-EE	35–43	5–20	0.5	2.6	Estrogen
Methylestradiol	17α-Methyl-17β-estradiol	70	44	?	?	Estrogen
Diethylstilbestrol	DES; Stilbestrol	129.5 (89.1–468)	219.63 (61.2–295)	0.04	0.05	Estrogen
Hexestrol	Dihydrodiethylstilbestrol	153.6 (31–302)	60–234	0.06	0.06	Estrogen
Dienestrol	Dehydrostilbestrol	37 (20.4–223)	56–404	0.05	0.03	Estrogen
Benzestrol (B2)	–	114	?	?	?	Estrogen
Chlorotrianisene	TACE	1.74	?	15.30	?	Estrogen
Triphenylethylene	TPE	0.074	?	?	?	Estrogen
Triphenylbromoethylene	TPBE	2.69	?	?	?	Estrogen
Tamoxifen	ICI-46,474	3 (0.1–47)	3.33 (0.28–6)	3.4–9.69	2.5	SERM
Afimoxifene	4-Hydroxytamoxifen; 4-OHT	100.1 (1.7–257)	10 (0.98–339)	2.3 (0.1–3.61)	0.04–4.8	SERM
Toremifene	4-Chlorotamoxifen; 4-CT	?	?	7.14–20.3	15.4	SERM
Clomifene	MRL-41	25 (19.2–37.2)	12	0.9	1.2	SERM
Cyclofenil	F-6066; Sexovid	151–152	243	?	?	SERM
Nafoxidine	U-11,000A	30.9–44	16	0.3	0.8	SERM
Raloxifene	–	41.2 (7.8–69)	5.34 (0.54–16)	0.188–0.52	20.2	SERM
Arzoxifene	LY-353,381	?	?	0.179	?	SERM
Lasofoxifene	CP-336,156	10.2–166	19.0	0.229	?	SERM
Ormeloxifene	Centchroman	?	?	0.313	?	SERM
Levormeloxifene	6720-CDRI; NNC-460,020	1.55	1.88	?	?	SERM
Ospemifene	Deaminohydroxytoremifene	0.82–2.63	0.59–1.22	?	?	SERM
Bazedoxifene	–	?	?	0.053	?	SERM
Etacstil	GW-5638	4.30	11.5	?	?	SERM
ICI-164,384	–	63.5 (3.70–97.7)	166	0.2	0.08	Antiestrogen
Fulvestrant	ICI-182,780	43.5 (9.4–325)	21.65 (2.05–40.5)	0.42	1.3	Antiestrogen
Propylpyrazoletriol	PPT	49 (10.0–89.1)	0.12	0.40	92.8	ERα agonist
16α-LE2	16α-Lactone-17β-estradiol	14.6–57	0.089	0.27	131	ERα agonist
16α-Iodo-E2	16α-Iodo-17β-estradiol	30.2	2.30	?	?	ERα agonist
Methylpiperidinopyrazole	MPP	11	0.05	?	?	ERα antagonist
Diarylpropionitrile	DPN	0.12–0.25	6.6–18	32.4	1.7	ERβ agonist
8β-VE2	8β-Vinyl-17β-estradiol	0.35	22.0–83	12.9	0.50	ERβ agonist
Prinaberel	ERB-041; WAY-202,041	0.27	67–72	?	?	ERβ agonist
ERB-196	WAY-202,196	?	180	?	?	ERβ agonist
Erteberel	SERBA-1; LY-500,307	?	?	2.68	0.19	ERβ agonist
SERBA-2	–	?	?	14.5	1.54	ERβ agonist
Coumestrol	–	9.225 (0.0117–94)	64.125 (0.41–185)	0.14–80.0	0.07–27.0	Xenoestrogen
Genistein	–	0.445 (0.0012–16)	33.42 (0.86–87)	2.6–126	0.3–12.8	Xenoestrogen
Equol	–	0.2–0.287	0.85 (0.10–2.85)	?	?	Xenoestrogen
Daidzein	–	0.07 (0.0018–9.3)	0.7865 (0.04–17.1)	2.0	85.3	Xenoestrogen
Biochanin A	–	0.04 (0.022–0.15)	0.6225 (0.010–1.2)	174	8.9	Xenoestrogen
Kaempferol	–	0.07 (0.029–0.10)	2.2 (0.002–3.00)	?	?	Xenoestrogen
Naringenin	–	0.0054 (<0.001–0.01)	0.15 (0.11–0.33)	?	?	Xenoestrogen
8-Prenylnaringenin	8-PN	4.4	?	?	?	Xenoestrogen
Quercetin	–	<0.001–0.01	0.002–0.040	?	?	Xenoestrogen
Ipriflavone	–	<0.01	<0.01	?	?	Xenoestrogen
Miroestrol	–	0.39	?	?	?	Xenoestrogen
Deoxymiroestrol	–	2.0	?	?	?	Xenoestrogen
β-Sitosterol	–	<0.001–0.0875	<0.001–0.016	?	?	Xenoestrogen
Resveratrol	–	<0.001–0.0032	?	?	?	Xenoestrogen
α-Zearalenol	–	48 (13–52.5)	?	?	?	Xenoestrogen
β-Zearalenol	–	0.6 (0.032–13)	?	?	?	Xenoestrogen
Zeranol	α-Zearalanol	48–111	?	?	?	Xenoestrogen
Taleranol	β-Zearalanol	16 (13–17.8)	14	0.8	0.9	Xenoestrogen
Zearalenone	ZEN	7.68 (2.04–28)	9.45 (2.43–31.5)	?	?	Xenoestrogen
Zearalanone	ZAN	0.51	?	?	?	Xenoestrogen
Bisphenol A	BPA	0.0315 (0.008–1.0)	0.135 (0.002–4.23)	195	35	Xenoestrogen
Endosulfan	EDS	<0.001–<0.01	<0.01	?	?	Xenoestrogen
Kepone	Chlordecone	0.0069–0.2	?	?	?	Xenoestrogen
o,p'-DDT	–	0.0073–0.4	?	?	?	Xenoestrogen
p,p'-DDT	–	0.03	?	?	?	Xenoestrogen
Methoxychlor	p,p'-Dimethoxy-DDT	0.01 (<0.001–0.02)	0.01–0.13	?	?	Xenoestrogen
HPTE	Hydroxychlor; p,p'-OH-DDT	1.2–1.7	?	?	?	Xenoestrogen
Testosterone	T; 4-Androstenolone	<0.0001–<0.01	<0.002–0.040	>5000	>5000	Androgen
Dihydrotestosterone	DHT; 5α-Androstanolone	0.01 (<0.001–0.05)	0.0059–0.17	221–>5000	73–1688	Androgen
Nandrolone	19-Nortestosterone; 19-NT	0.01	0.23	765	53	Androgen
Dehydroepiandrosterone	DHEA; Prasterone	0.038 (<0.001–0.04)	0.019–0.07	245–1053	163–515	Androgen
5-Androstenediol	A5; Androstenediol	6	17	3.6	0.9	Androgen
4-Androstenediol	–	0.5	0.6	23	19	Androgen
4-Androstenedione	A4; Androstenedione	<0.01	<0.01	>10000	>10000	Androgen
3α-Androstanediol	3α-Adiol	0.07	0.3	260	48	Androgen
3β-Androstanediol	3β-Adiol	3	7	6	2	Androgen
Androstanedione	5α-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Etiocholanedione	5β-Androstanedione	<0.01	<0.01	>10000	>10000	Androgen
Methyltestosterone	17α-Methyltestosterone	<0.0001	?	?	?	Androgen
Ethinyl-3α-androstanediol	17α-Ethynyl-3α-adiol	4.0	<0.07	?	?	Estrogen
Ethinyl-3β-androstanediol	17α-Ethynyl-3β-adiol	50	5.6	?	?	Estrogen
Progesterone	P4; 4-Pregnenedione	<0.001–0.6	<0.001–0.010	?	?	Progestogen
Norethisterone	NET; 17α-Ethynyl-19-NT	0.085 (0.0015–<0.1)	0.1 (0.01–0.3)	152	1084	Progestogen
Norethynodrel	5(10)-Norethisterone	0.5 (0.3–0.7)	<0.1–0.22	14	53	Progestogen
Tibolone	7α-Methylnorethynodrel	0.5 (0.45–2.0)	0.2–0.076	?	?	Progestogen
Δ⁴-Tibolone	7α-Methylnorethisterone	0.069–<0.1	0.027–<0.1	?	?	Progestogen
3α-Hydroxytibolone	–	2.5 (1.06–5.0)	0.6–0.8	?	?	Progestogen
3β-Hydroxytibolone	–	1.6 (0.75–1.9)	0.070–0.1	?	?	Progestogen
Footnotes: ^a = (1) Binding affinity values are of the format "median (range)" (# (#–#)), "range" (#–#), or "value" (#) depending on the values available. The full sets of values within the ranges can be found in the Wiki code. (2) Binding affinities were determined via displacement studies in a variety of in-vitro systems with labeled estradiol and human ERα and ERβ proteins (except the ERβ values from Kuiper et al. (1997), which are rat ERβ). Sources: See template page.

Binding and functional selectivity

The ER's helix 12 domain plays a crucial role in determining interactions with coactivators and corepressors and, therefore, the respective agonist or antagonist effect of the ligand.[13][14]

Different ligands may differ in their affinity for alpha and beta isoforms of the estrogen receptor:

estradiol binds equally well to both receptors[15]
estrone, and raloxifene bind preferentially to the alpha receptor[15]
estriol, and genistein to the beta receptor[15]

Subtype selective estrogen receptor modulators preferentially bind to either the α- or the β-subtype of the receptor. In addition, the different estrogen receptor combinations may respond differently to various ligands, which may translate into tissue selective agonistic and antagonistic effects.[16] The ratio of α- to β- subtype concentration has been proposed to play a role in certain diseases.[17]

The concept of selective estrogen receptor modulators is based on the ability to promote ER interactions with different proteins such as transcriptional coactivator or corepressors. Furthermore, the ratio of coactivator to corepressor protein varies in different tissues.[18] As a consequence, the same ligand may be an agonist in some tissue (where coactivators predominate) while antagonistic in other tissues (where corepressors dominate). Tamoxifen, for example, is an antagonist in breast and is, therefore, used as a breast cancer treatment[19] but an ER agonist in bone (thereby preventing osteoporosis) and a partial agonist in the endometrium (increasing the risk of uterine cancer).

Signal transduction

Since estrogen is a steroidal hormone, it can pass through the phospholipid membranes of the cell, and receptors therefore do not need to be membrane-bound in order to bind with estrogen.

Genomic

In the absence of hormone, estrogen receptors are largely located in the cytosol. Hormone binding to the receptor triggers a number of events starting with migration of the receptor from the cytosol into the nucleus, dimerization of the receptor, and subsequent binding of the receptor dimer to specific sequences of DNA known as hormone response elements. The DNA/receptor complex then recruits other proteins that are responsible for the transcription of downstream DNA into mRNA and finally protein that results in a change in cell function. Estrogen receptors also occur within the cell nucleus, and both estrogen receptor subtypes have a DNA-binding domain and can function as transcription factors to regulate the production of proteins.

The receptor also interacts with activator protein 1 and Sp-1 to promote transcription, via several coactivators such as PELP-1.[2]

Direct acetylation of the estrogen receptor alpha at the lysine residues in hinge region by p300 regulates transactivation and hormone sensitivity.[20]

Non-genomic

Some estrogen receptors associate with the cell surface membrane and can be rapidly activated by exposure of cells to estrogen.[21][22]

In addition, some ER may associate with cell membranes by attachment to caveolin-1 and form complexes with G proteins, striatin, receptor tyrosine kinases (e.g., EGFR and IGF-1), and non-receptor tyrosine kinases (e.g., Src).[2][21] Through striatin, some of this membrane bound ER may lead to increased levels of Ca²⁺ and nitric oxide (NO).[23] Through the receptor tyrosine kinases, signals are sent to the nucleus through the mitogen-activated protein kinase (MAPK/ERK) pathway and phosphoinositide 3-kinase (Pl3K/AKT) pathway.[24] Glycogen synthase kinase-3 (GSK)-3β inhibits transcription by nuclear ER by inhibiting phosphorylation of serine 118 of nuclear ERα. Phosphorylation of GSK-3β removes its inhibitory effect, and this can be achieved by the PI3K/AKT pathway and the MAPK/ERK pathway, via rsk.

17β-Estradiol has been shown to activate the G protein-coupled receptor GPR30.[25] However the subcellular localization and role of this receptor are still object of controversy.[26]

Disease

Nolvadex (tamoxifen) 20 mg

Arimidex (anastrozole) 1 mg

Cancer

Estrogen receptors are over-expressed in around 70% of breast cancer cases, referred to as "ER-positive", and can be demonstrated in such tissues using immunohistochemistry. Two hypotheses have been proposed to explain why this causes tumorigenesis, and the available evidence suggests that both mechanisms contribute:

First, binding of estrogen to the ER stimulates proliferation of mammary cells, with the resulting increase in cell division and DNA replication, leading to mutations.
Second, estrogen metabolism produces genotoxic waste.

The result of both processes is disruption of cell cycle, apoptosis and DNA repair, which increases the chance of tumour formation. ERα is certainly associated with more differentiated tumours, while evidence that ERβ is involved is controversial. Different versions of the ESR1 gene have been identified (with single-nucleotide polymorphisms) and are associated with different risks of developing breast cancer.[19]

Estrogen and the ERs have also been implicated in breast cancer, ovarian cancer, colon cancer, prostate cancer, and endometrial cancer. Advanced colon cancer is associated with a loss of ERβ, the predominant ER in colon tissue, and colon cancer is treated with ERβ-specific agonists.[27]

Endocrine therapy for breast cancer involves selective estrogen receptor modulators (SERMS), such as tamoxifen, which behave as ER antagonists in breast tissue, or aromatase inhibitors, such as anastrozole. ER status is used to determine sensitivity of breast cancer lesions to tamoxifen and aromatase inhibitors.[28] Another SERM, raloxifene, has been used as a preventive chemotherapy for women judged to have a high risk of developing breast cancer.[29] Another chemotherapeutic anti-estrogen, ICI 182,780 (Faslodex), which acts as a complete antagonist, also promotes degradation of the estrogen receptor.

However, de novo resistance to endocrine therapy undermines the efficacy of using competitive inhibitors like tamoxifen. Hormone deprivation through the use of aromatase inhibitors is also rendered futile.[30] Massively parallel genome sequencing has revealed the common presence of point mutations on ESR1 that are drivers for resistance, and promote the agonist conformation of ERα without the bound ligand. Such constitutive, estrogen-independent activity is driven by specific mutations, such as the D538G or Y537S/C/N mutations, in the ligand binding domain of ESR1 and promote cell proliferation and tumor progression without hormone stimulation.[31]

Menopause

The metabolic effects of estrogen in postmenopausal women has been linked to the genetic polymorphism of estrogen receptor beta (ER-β).[32]

Aging

Studies in female mice have shown that estrogen receptor-alpha declines in the pre-optic hypothalamus as they grow old. Female mice that were given a calorically restricted diet during the majority of their lives maintained higher levels of ERα in the pre-optic hypothalamus than their non-calorically restricted counterparts.[8]

Obesity

A dramatic demonstration of the importance of estrogens in the regulation of fat deposition comes from transgenic mice that were genetically engineered to lack a functional aromatase gene. These mice have very low levels of estrogen and are obese.[33] Obesity was also observed in estrogen deficient female mice lacking the follicle-stimulating hormone receptor.[34] The effect of low estrogen on increased obesity has been linked to estrogen receptor alpha.[35]

Discovery

Estrogen receptors were first identified by Elwood V. Jensen at the University of Chicago in 1958,[36][37] for which Jensen was awarded the Lasker Award.[38] The gene for a second estrogen receptor (ERβ) was identified in 1996 by Kuiper et al. in rat prostate and ovary using degenerate ERalpha primers.[39]

References

Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (Dec 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 58 (4): 773–81. doi:10.1124/pr.58.4.8. PMID 17132854. S2CID 45996586.
Levin ER (Aug 2005). "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology. 19 (8): 1951–9. doi:10.1210/me.2004-0390. PMC 1249516. PMID 15705661.
Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (Sep 2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Molecular and Cellular Biology. 24 (17): 7681–94. doi:10.1128/MCB.24.17.7681-7694.2004. PMC 506997. PMID 15314175.
Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA (Oct 2001). "Mechanisms of estrogen action". Physiological Reviews. 81 (4): 1535–65. doi:10.1152/physrev.2001.81.4.1535. PMID 11581496.
Leung YK, Mak P, Hassan S, Ho SM (Aug 2006). "Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13162–7. doi:10.1073/pnas.0605676103. PMC 1552044. PMID 16938840.
Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P (Sep 2000). "Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10751–6. doi:10.1073/pnas.97.20.10751. PMC 27095. PMID 11005855.
Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (Nov 1997). "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology. 138 (11): 4613–21. doi:10.1210/en.138.11.4613. PMID 9348186.
Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H (Jun 2005). "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice" (PDF). Neuro Endocrinology Letters. 26 (3): 197–203. PMID 15990721.
Hess RA (Jul 2003). "Estrogen in the adult male reproductive tract: a review". Reproductive Biology and Endocrinology. 1 (52): 52. doi:10.1186/1477-7827-1-52. PMC 179885. PMID 12904263.
Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA (Feb 2002). "Estrogenic hormone action in the heart: regulatory network and function". Cardiovascular Research. 53 (3): 709–19. doi:10.1016/S0008-6363(01)00526-0. PMID 11861041.
Htun H, Holth LT, Walker D, Davie JR, Hager GL (Feb 1999). "Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor". Molecular Biology of the Cell. 10 (2): 471–86. doi:10.1091/mbc.10.2.471. PMC 25181. PMID 9950689.
Pfeffer U, Fecarotta E, Vidali G (May 1995). "Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells". Cancer Research. 55 (10): 2158–65. PMID 7743517.
Ascenzi P, Bocedi A, Marino M (Aug 2006). "Structure-function relationship of estrogen receptor alpha and beta: impact on human health". Molecular Aspects of Medicine. 27 (4): 299–402. doi:10.1016/j.mam.2006.07.001. PMID 16914190.
Bourguet W, Germain P, Gronemeyer H (Oct 2000). "Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications". Trends in Pharmacological Sciences. 21 (10): 381–8. doi:10.1016/S0165-6147(00)01548-0. PMID 11050318.
Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR (Sep 2006). "Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding". Endocrinology. 147 (9): 4132–50. doi:10.1210/en.2006-0113. PMID 16728493.
Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N (Jul 2005). "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release". Molecular and Cellular Endocrinology. 239 (1–2): 27–36. doi:10.1016/j.mce.2005.04.008. PMID 15950373. S2CID 42052008.
Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V (Nov 2008). "Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness". Fertility and Sterility. 90 (5): 1878–85. doi:10.1016/j.fertnstert.2007.09.019. PMID 18166184.
Shang Y, Brown M (Mar 2002). "Molecular determinants for the tissue specificity of SERMs". Science. 295 (5564): 2465–8. doi:10.1126/science.1068537. PMID 11923541. S2CID 30634073.
Deroo BJ, Korach KS (Mar 2006). "Estrogen receptors and human disease". The Journal of Clinical Investigation. 116 (3): 561–70. doi:10.1172/JCI27987. PMC 2373424. PMID 16511588.
Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG (May 2001). "Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity". The Journal of Biological Chemistry. 276 (21): 18375–83. doi:10.1074/jbc.M100800200. PMID 11279135.
Zivadinovic D, Gametchu B, Watson CS (2005). "Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses". Breast Cancer Research. 7 (1): R101–12. doi:10.1186/bcr958. PMC 1064104. PMID 15642158.
Björnström L, Sjöberg M (Jun 2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nuclear Receptor. 2 (1): 3. doi:10.1186/1478-1336-2-3. PMC 434532. PMID 15196329.
Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH (Dec 2004). "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha". Proceedings of the National Academy of Sciences of the United States of America. 101 (49): 17126–31. doi:10.1073/pnas.0407492101. PMC 534607. PMID 15569929.
Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P (Dec 1995). "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase". Science. 270 (5241): 1491–4. doi:10.1126/science.270.5241.1491. PMID 7491495. S2CID 4662264.
Prossnitz ER, Arterburn JB, Sklar LA (Feb 2007). "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology. 265–266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610. PMID 17222505.
Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier KH (Oct 2008). "G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol". Endocrinology. 149 (10): 4846–56. doi:10.1210/en.2008-0269. PMID 18566127.
Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC (Oct 2003). "Evaluation of an estrogen receptor-beta agonist in animal models of human disease". Endocrinology. 144 (10): 4241–9. doi:10.1210/en.2003-0550. PMID 14500559.
Clemons M, Danson S, Howell A (Aug 2002). "Tamoxifen ("Nolvadex"): a review". Cancer Treatment Reviews. 28 (4): 165–80. doi:10.1016/s0305-7372(02)00036-1. PMID 12363457.
Fabian CJ, Kimler BF (Mar 2005). "Selective estrogen-receptor modulators for primary prevention of breast cancer". Journal of Clinical Oncology. 23 (8): 1644–55. doi:10.1200/JCO.2005.11.005. PMID 15755972.
Oesterreich S, Davidson NE (Dec 2013). "The search for ESR1 mutations in breast cancer". Nature Genetics. 45 (12): 1415–6. doi:10.1038/ng.2831. PMC 4934882. PMID 24270445.
Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al. (Sep 2013). "Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts". Cell Reports. 4 (6): 1116–30. doi:10.1016/j.celrep.2013.08.022. PMC 3881975. PMID 24055055.
Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.
Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER (Sep 2003). "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis". Endocrinology. 144 (9): 3895–903. doi:10.1210/en.2003-0244. PMID 12933663.
Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR (Nov 2000). "Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice". Endocrinology. 141 (11): 4295–308. doi:10.1210/en.141.11.4295. PMID 11089565.
Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA (Nov 2000). "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice". Biochemical and Biophysical Research Communications. 278 (3): 640–5. doi:10.1006/bbrc.2000.3827. PMID 11095962.
Jensen EV, Jordan VC (Jun 2003). "The estrogen receptor: a model for molecular medicine" (abstract). Clinical Cancer Research. 9 (6): 1980–9. PMID 12796359.
Jensen E (2011). "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology. 74: 1–11. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507.
David Bracey, 2004 "UC Scientist Wins 'American Nobel' Research Award." University of Cincinnati press release.
Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (Jun 1996). "Cloning of a novel receptor expressed in rat prostate and ovary". Proceedings of the National Academy of Sciences of the United States of America. 93 (12): 5925–30. doi:10.1073/pnas.93.12.5925. PMC 39164. PMID 8650195.

External links

Estrogen Receptors at the US National Library of Medicine Medical Subject Headings (MeSH)
David S. Goodsell (2003-09-01). "Estrogen Receptor". Protein Data Bank, Research Collaboratory for Structural Bioinformatics (RCSB). Retrieved 2008-03-15.

This article is issued from Wikipedia. The text is licensed under Creative Commons - Attribution - Sharealike. Additional terms may apply for the media files.

[pmid17132854-1] Dahlman-Wright K, Cavailles V, Fuqua SA, Jordan VC, Katzenellenbogen JA, Korach KS, Maggi A, Muramatsu M, Parker MG, Gustafsson JA (Dec 2006). "International Union of Pharmacology. LXIV. Estrogen receptors". Pharmacological Reviews. 58 (4): 773–81. doi:10.1124/pr.58.4.8. PMID 17132854. S2CID 45996586.

[pmid15705661-2] Levin ER (Aug 2005). "Integration of the extranuclear and nuclear actions of estrogen". Molecular Endocrinology. 19 (8): 1951–9. doi:10.1210/me.2004-0390. PMC 1249516. PMID 15705661.

[pmid15314175-3] Li X, Huang J, Yi P, Bambara RA, Hilf R, Muyan M (Sep 2004). "Single-chain estrogen receptors (ERs) reveal that the ERalpha/beta heterodimer emulates functions of the ERalpha dimer in genomic estrogen signaling pathways". Molecular and Cellular Biology. 24 (17): 7681–94. doi:10.1128/MCB.24.17.7681-7694.2004. PMC 506997. PMID 15314175.

[4] Nilsson S, Mäkelä S, Treuter E, Tujague M, Thomsen J, Andersson G, Enmark E, Pettersson K, Warner M, Gustafsson JA (Oct 2001). "Mechanisms of estrogen action". Physiological Reviews. 81 (4): 1535–65. doi:10.1152/physrev.2001.81.4.1535. PMID 11581496.

[5] Leung YK, Mak P, Hassan S, Ho SM (Aug 2006). "Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling". Proceedings of the National Academy of Sciences of the United States of America. 103 (35): 13162–7. doi:10.1073/pnas.0605676103. PMC 1552044. PMID 16938840.

[6] Hawkins MB, Thornton JW, Crews D, Skipper JK, Dotte A, Thomas P (Sep 2000). "Identification of a third distinct estrogen receptor and reclassification of estrogen receptors in teleosts". Proceedings of the National Academy of Sciences of the United States of America. 97 (20): 10751–6. doi:10.1073/pnas.97.20.10751. PMC 27095. PMID 11005855.

[pmid9348186-7] Couse JF, Lindzey J, Grandien K, Gustafsson JA, Korach KS (Nov 1997). "Tissue distribution and quantitative analysis of estrogen receptor-alpha (ERalpha) and estrogen receptor-beta (ERbeta) messenger ribonucleic acid in the wild-type and ERalpha-knockout mouse". Endocrinology. 138 (11): 4613–21. doi:10.1210/en.138.11.4613. PMID 9348186.

[pmid15990721-8] Yaghmaie F, Saeed O, Garan SA, Freitag W, Timiras PS, Sternberg H (Jun 2005). "Caloric restriction reduces cell loss and maintains estrogen receptor-alpha immunoreactivity in the pre-optic hypothalamus of female B6D2F1 mice" (PDF). Neuro Endocrinology Letters. 26 (3): 197–203. PMID 15990721.

[pmid12904263-9] Hess RA (Jul 2003). "Estrogen in the adult male reproductive tract: a review". Reproductive Biology and Endocrinology. 1 (52): 52. doi:10.1186/1477-7827-1-52. PMC 179885. PMID 12904263.

[pmid11861041-10] Babiker FA, De Windt LJ, van Eickels M, Grohe C, Meyer R, Doevendans PA (Feb 2002). "Estrogenic hormone action in the heart: regulatory network and function". Cardiovascular Research. 53 (3): 709–19. doi:10.1016/S0008-6363(01)00526-0. PMID 11861041.

[11] Htun H, Holth LT, Walker D, Davie JR, Hager GL (Feb 1999). "Direct visualization of the human estrogen receptor alpha reveals a role for ligand in the nuclear distribution of the receptor". Molecular Biology of the Cell. 10 (2): 471–86. doi:10.1091/mbc.10.2.471. PMC 25181. PMID 9950689.

[12] Pfeffer U, Fecarotta E, Vidali G (May 1995). "Coexpression of multiple estrogen receptor variant messenger RNAs in normal and neoplastic breast tissues and in MCF-7 cells". Cancer Research. 55 (10): 2158–65. PMID 7743517.

[13] Ascenzi P, Bocedi A, Marino M (Aug 2006). "Structure-function relationship of estrogen receptor alpha and beta: impact on human health". Molecular Aspects of Medicine. 27 (4): 299–402. doi:10.1016/j.mam.2006.07.001. PMID 16914190.

[14] Bourguet W, Germain P, Gronemeyer H (Oct 2000). "Nuclear receptor ligand-binding domains: three-dimensional structures, molecular interactions and pharmacological implications". Trends in Pharmacological Sciences. 21 (10): 381–8. doi:10.1016/S0165-6147(00)01548-0. PMID 11050318.

[pmid16728493-15] Zhu BT, Han GZ, Shim JY, Wen Y, Jiang XR (Sep 2006). "Quantitative structure-activity relationship of various endogenous estrogen metabolites for human estrogen receptor alpha and beta subtypes: Insights into the structural determinants favoring a differential subtype binding". Endocrinology. 147 (9): 4132–50. doi:10.1210/en.2006-0113. PMID 16728493.

[pmid15950373-16] Kansra S, Yamagata S, Sneade L, Foster L, Ben-Jonathan N (Jul 2005). "Differential effects of estrogen receptor antagonists on pituitary lactotroph proliferation and prolactin release". Molecular and Cellular Endocrinology. 239 (1–2): 27–36. doi:10.1016/j.mce.2005.04.008. PMID 15950373. S2CID 42052008.

[pmid18166184-17] Bakas P, Liapis A, Vlahopoulos S, Giner M, Logotheti S, Creatsas G, Meligova AK, Alexis MN, Zoumpourlis V (Nov 2008). "Estrogen receptor alpha and beta in uterine fibroids: a basis for altered estrogen responsiveness". Fertility and Sterility. 90 (5): 1878–85. doi:10.1016/j.fertnstert.2007.09.019. PMID 18166184.

[Shang_2002-18] Shang Y, Brown M (Mar 2002). "Molecular determinants for the tissue specificity of SERMs". Science. 295 (5564): 2465–8. doi:10.1126/science.1068537. PMID 11923541. S2CID 30634073.

[pmid16511588-19] Deroo BJ, Korach KS (Mar 2006). "Estrogen receptors and human disease". The Journal of Clinical Investigation. 116 (3): 561–70. doi:10.1172/JCI27987. PMC 2373424. PMID 16511588.

[pmid11279135-20] Wang C, Fu M, Angeletti RH, Siconolfi-Baez L, Reutens AT, Albanese C, Lisanti MP, Katzenellenbogen BS, Kato S, Hopp T, Fuqua SA, Lopez GN, Kushner PJ, Pestell RG (May 2001). "Direct acetylation of the estrogen receptor alpha hinge region by p300 regulates transactivation and hormone sensitivity". The Journal of Biological Chemistry. 276 (21): 18375–83. doi:10.1074/jbc.M100800200. PMID 11279135.

[pmid15642158-21] Zivadinovic D, Gametchu B, Watson CS (2005). "Membrane estrogen receptor-alpha levels in MCF-7 breast cancer cells predict cAMP and proliferation responses". Breast Cancer Research. 7 (1): R101–12. doi:10.1186/bcr958. PMC 1064104. PMID 15642158.

[Björnström_2004-22] Björnström L, Sjöberg M (Jun 2004). "Estrogen receptor-dependent activation of AP-1 via non-genomic signalling". Nuclear Receptor. 2 (1): 3. doi:10.1186/1478-1336-2-3. PMC 434532. PMID 15196329.

[pmid15569929-23] Lu Q, Pallas DC, Surks HK, Baur WE, Mendelsohn ME, Karas RH (Dec 2004). "Striatin assembles a membrane signaling complex necessary for rapid, nongenomic activation of endothelial NO synthase by estrogen receptor alpha". Proceedings of the National Academy of Sciences of the United States of America. 101 (49): 17126–31. doi:10.1073/pnas.0407492101. PMC 534607. PMID 15569929.

[pmid7491495-24] Kato S, Endoh H, Masuhiro Y, Kitamoto T, Uchiyama S, Sasaki H, Masushige S, Gotoh Y, Nishida E, Kawashima H, Metzger D, Chambon P (Dec 1995). "Activation of the estrogen receptor through phosphorylation by mitogen-activated protein kinase". Science. 270 (5241): 1491–4. doi:10.1126/science.270.5241.1491. PMID 7491495. S2CID 4662264.

[pmid17222505-25] Prossnitz ER, Arterburn JB, Sklar LA (Feb 2007). "GPR30: A G protein-coupled receptor for estrogen". Molecular and Cellular Endocrinology. 265–266: 138–42. doi:10.1016/j.mce.2006.12.010. PMC 1847610. PMID 17222505.

[pmid18566127-26] Otto C, Rohde-Schulz B, Schwarz G, Fuchs I, Klewer M, Brittain D, Langer G, Bader B, Prelle K, Nubbemeyer R, Fritzemeier KH (Oct 2008). "G protein-coupled receptor 30 localizes to the endoplasmic reticulum and is not activated by estradiol". Endocrinology. 149 (10): 4846–56. doi:10.1210/en.2008-0269. PMID 18566127.

[pmid14500559-27] Harris HA, Albert LM, Leathurby Y, Malamas MS, Mewshaw RE, Miller CP, Kharode YP, Marzolf J, Komm BS, Winneker RC, Frail DE, Henderson RA, Zhu Y, Keith JC (Oct 2003). "Evaluation of an estrogen receptor-beta agonist in animal models of human disease". Endocrinology. 144 (10): 4241–9. doi:10.1210/en.2003-0550. PMID 14500559.

[pmid12363457-28] Clemons M, Danson S, Howell A (Aug 2002). "Tamoxifen ("Nolvadex"): a review". Cancer Treatment Reviews. 28 (4): 165–80. doi:10.1016/s0305-7372(02)00036-1. PMID 12363457.

[pmid15755972-29] Fabian CJ, Kimler BF (Mar 2005). "Selective estrogen-receptor modulators for primary prevention of breast cancer". Journal of Clinical Oncology. 23 (8): 1644–55. doi:10.1200/JCO.2005.11.005. PMID 15755972.

[30] Oesterreich S, Davidson NE (Dec 2013). "The search for ESR1 mutations in breast cancer". Nature Genetics. 45 (12): 1415–6. doi:10.1038/ng.2831. PMC 4934882. PMID 24270445.

[31] Li S, Shen D, Shao J, Crowder R, Liu W, Prat A, et al. (Sep 2013). "Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts". Cell Reports. 4 (6): 1116–30. doi:10.1016/j.celrep.2013.08.022. PMC 3881975. PMID 24055055.

[pmid21117950-32] Darabi M, Ani M, Panjehpour M, Rabbani M, Movahedian A, Zarean E (2011). "Effect of estrogen receptor β A1730G polymorphism on ABCA1 gene expression response to postmenopausal hormone replacement therapy". Genetic Testing and Molecular Biomarkers. 15 (1–2): 11–5. doi:10.1089/gtmb.2010.0106. PMID 21117950.

[pmid12933663-33] Hewitt KN, Boon WC, Murata Y, Jones ME, Simpson ER (Sep 2003). "The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis". Endocrinology. 144 (9): 3895–903. doi:10.1210/en.2003-0244. PMID 12933663.

[pmid11089565-34] Danilovich N, Babu PS, Xing W, Gerdes M, Krishnamurthy H, Sairam MR (Nov 2000). "Estrogen deficiency, obesity, and skeletal abnormalities in follicle-stimulating hormone receptor knockout (FORKO) female mice". Endocrinology. 141 (11): 4295–308. doi:10.1210/en.141.11.4295. PMID 11089565.

[pmid11095962-35] Ohlsson C, Hellberg N, Parini P, Vidal O, Bohlooly-Y M, Bohlooly M, Rudling M, Lindberg MK, Warner M, Angelin B, Gustafsson JA (Nov 2000). "Obesity and disturbed lipoprotein profile in estrogen receptor-alpha-deficient male mice". Biochemical and Biophysical Research Communications. 278 (3): 640–5. doi:10.1006/bbrc.2000.3827. PMID 11095962.

[pmid12796359-36] Jensen EV, Jordan VC (Jun 2003). "The estrogen receptor: a model for molecular medicine" (abstract). Clinical Cancer Research. 9 (6): 1980–9. PMID 12796359.

[pmid21888507-37] Jensen E (2011). "A conversation with Elwood Jensen. Interview by David D. Moore". Annual Review of Physiology. 74: 1–11. doi:10.1146/annurev-physiol-020911-153327. PMID 21888507.

[38] David Bracey, 2004 "UC Scientist Wins 'American Nobel' Research Award." University of Cincinnati press release.

[pmid8650195-39] Kuiper GG, Enmark E, Pelto-Huikko M, Nilsson S, Gustafsson JA (Jun 1996). "Cloning of a novel receptor expressed in rat prostate and ovary". Proceedings of the National Academy of Sciences of the United States of America. 93 (12): 5925–30. doi:10.1073/pnas.93.12.5925. PMC 39164. PMID 8650195.